Investigation has focused in the mechanisms of interaction between corticosterone releasing hormone (CRH) and other regulators in the control of the hypothalamic-pituitary-adrenal axis in normal conditions and during adaptation to stress. Studies during aging in two strains of rats which differ in their responsiveness to stress, showed reduced concentration of pituitary CRH receptors in old rats. Despite the decrease in receptors in both strains, basal and stress stimulated ACTH were comparable to those in young rats. However, stress induced corticosterone responses were more prolonged in old rats. These data suggest that a defect in adrenal responsiveness to ACTH may have an important role in the alterations of the hypothalamic-pituitary adrenal axis during aging. Previous studies showed that sustained stress is accompanied by decreases in pituitary CRH receptors and pituitary desensitization to the primary stress, but a hypersensitivity to a novel stress. The role of CRH and VP on these changes were studied by analysis of plasma ACTH and corticosterone responses to acute stress in rats receiving chronic minipump infusions of CRH alone or in combination with VP. CRH and CRH plus VP infusion caused the expected decrease in CRH receptors, but in contrast with the changes in chronic stress, ACTH responses to acute stress were markedly reduced in rats receiving the infusions. Plasma ACTH responses to acute CRH or CRH plus VP injection, as well as releasable ACTH pools measured in vitro by stimulation with 40 mM KCL were also reduced following chronic CRH treatment. The data indicate that sustained pituitary account for the enhanced ACTH responses to a novel stimulus during chronic stress. Studies in forebrain neuronal cell cultures showed that CRH stimulates cyclic AMP production. Similar to the pituitary, this effect was enhanced by the protein kinase C stimulators VP and phorbol esters, and inhibited by glucocorticoids. The data supports a role for CRH in the regulation of extrahypothalamic neuronal function.